U.S. Pat. No. 5,492,906 discloses synthesis and use of several derivatives of thieno-triazolo-diazepine, including tetrahydro-4,7,8,10 methyl-1(chloro-2 phenyl)-6 (methoxy-4 phenyl-carbamoyl)-9 pyrido[4′,3′-4,5]thieno[3,2-f]triazolo-1,2,4[4,3-a] diazepine-1,4. However, the syntheis is different from that reported below.
The derivative of thienotriazolodiazepene of interest when synthesized by the method disclosed in U.S. Pat. No. 5,492,906 has been described in the literature as a platelet-activiating factor antagonist and named BN-50730.
Age-related macular degeneration involves a complex pathophysiology characterized by photoreceptor cell death and in some cases also pathological neovascularization.
Retinitis Pigmentosa is an inherited form of retinal degeneration that has been linked to mutations in several genes. Blindness occurs due to the selective death of photoreceptor cells.
Diabetic retinopathy involves pathological neovascularization that leads to functional impairments in the retina and eventually to retinal detachment.
Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a membrane-derived second messenger that is a potent mediator of inflammatory, ischemic, and immunological responses. PAF is rapidly produced in tissues in response to injury and other forms of stimulation. See N. G. Bazan et al., “A Platelet-activating factor and retinoic acid synergistically activate the inducible prostaglandin synthase gene,” Proc. Natl. Acad. Sci. USA, vol. 91, pp. 5252-5256 (1994). Intracellular and cell surface binding sites for PAF have been identified and distinguished by using diverse PAF antagonists that show a preference for one or more of the binding sites. See V. L. Marcheselli et al., “A Distinct platelet-activating factor binding sites in synaptic endings and intracellular membranes of rat cerebral cortex,” Journal of Biological Chemistry, vol. 265, pp. 9140-9145 (1990). Two binding sites found were associated with microsomal intracellular membranes and a third binding site was associated with the synaptosomal membrane (the extracellular plasma membrane). One of the internal microsomal binding sites displays the highest known affinity for PAF.
Several PAF antagonists have been identified. Most of the antagonists are competitive in nature. The antagonists can be divided into three distinct groups: PAF-related compounds such as CV 3988; synthetic PAF-unrelated compounds such as WEB 2086 and SR 27417; and natural products including BN-52021. See A. L. A. Pires et al., “A Long-lasting inhibitory activity of the hetrazepinic BN-50730 on exudation and cellular alterations evoked by PAF and LPS,” Br. J. Pharmacol., vol. 113, pp. 994-1000 (1994). A unique PAF antagonist, BN-50730, a hetrazepine, is known to displace PAF from microsomal membranes, but not from the synaptosomal, plasma membrane. See V. L. Marcheselli and N. G. Bazan, “A Platelet-activating factor is a messenger in the electroconvulsive shock-induced transcriptional activation of c-fos and zif-268 in hippocampus,” Journal of Neuroscience Research. vol. 37, pp. 54-61 (1994). Moreover, BN-50730 and WEB 2086, another PAF antagonist, are known to have different dissociation kinetics. See C. L. Silva et al., “A Formation of a highly stable complex between BN-50730 [tetrahydro-4,7,8,10 methyl-1(chloro-2 phenyl)-6 (methoxy-4 phenyl-carbamoyl)-9 pyrido[4′,3′-4,5]thieno[3,2-f]triazolo-1,2,4[4,3-a]diazepine-1,4] and the platelet-activating factor receptor in rabbit platelet membranes,” Biochemical Pharmacology, vol. 51, pp. 193-196 (1996).